benefits of the mediterranean diet: insights from the
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Title: Benefits of the Mediterranean Diet: Insights from the PREDIMED Study
Running title: PREDIMED and the Mediterranean Diet
Miguel A. Martínez-González [1,2,3], Jordi Salas-Salvadó [2,3,4], Ramón Estruch
[2,3,5], Dolores Corella D [3,6], Montse Fitó [3,7], Emilio Ros [3,5] for the
PREDIMED INVESTIGATORS*
1 Department of Preventive Medicine and Public Health, University of Navarra,
IDISNA (Navarra Health Research Institute), Pamplona, Spain.
2 The PREDIMED Research Network (RD 06/0045), Instituto de Salud Carlos III,
Madrid, Spain.
3 Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición
(CIBERobn), Instituto de Salud Carlos III, Madrid, Spain.
4 Human Nutrition Department, Hospital Universitari Sant Joan, Institut d'Investigació
Sanitaria Pere Virgili, Universitat Rovira i Virgili, Reus.
5 Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clinic, University
of Barcelona, Barcelona.
6 Department of Preventive Medicine and Public Health, University of Valencia,
Valencia.
7 Cardiovascular and Nutrition Research Group, Institut de Recerca Hospital del Mar,
Barcelona.
*A complete list of PREDIMED INVESTIGATORS can be found at the end of this
manuscript.
Last names for PubMed indexing: Martinez-Gonzalez, Salas-Salvado, Estruch,
Corella, Fito, Ros
Word count: 3053 (excluding title page, abstract and references)
Number of figures: 1 Number of Tables: 3
Correspondence and reprints:
Prof. Miguel Á. Martínez-González, MD, MPH, PhD. Department of Preventive
Medicine & Public Health, School of Medicine, University of Navarra, Irunlarrea 1,
31008-Pamplona, Navarra (Spain). E-mail: [email protected]. Tel: +34 948 42 56
00 Ext: 806463. Fax: + 34 948 42 57 40.
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Funding Disclosure: Supported by the official funding agency for biomedical research
of the Spanish government, Instituto de Salud Carlos III (ISCIII), through grants
provided to research networks specifically developed for the trial (RTIC G03/140, to
Dr. Estruch; RTIC RD 06/0045, to Dr. Martínez-González and through Centro de
Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición
(CIBERobn), and by grants from Centro Nacional de Investigaciones Cardiovasculares
(CNIC 06/2007), Fondo de Investigación Sanitaria–Fondo Europeo de Desarrollo
Regional (PI04-2239, PI 05/2584, CP06/00100, PI07/0240, PI07/1138, PI07/0954, PI
07/0473, PI10/01407, PI10/02658, PI11/01647, P11/02505 and PI13/01090), Ministerio
de Ciencia e Innovación (AGL-2009-13906-C02 and AGL2010-22319-C03), Fundación
Mapfre 2010, Consejería de Salud de la Junta de Andalucía (PI0105/2007), Public
Health Division of the Department of Health of the Autonomous Government of
Catalonia, Generalitat Valenciana (ACOMP06109, GVACOMP2010-181,
GVACOMP2011-151, ACOMP/2013/165, ACOMP/2013/159, CS2010-AP-111, and
CS2011-AP-042), and Regional Government of Navarra (P27/2011).
Role of the Funders: funding sources had no role in the design and conduct of the
study; collection, management, analysis, and interpretation of the data; and preparation,
review, or approval of the manuscript.
Conflicts of interest: MA Martinez-Gonzalez received grants for research from the
International Nut Council, Reus, Spain; J. Salas-Salvado has received grants for
research from the International Nut Council, Reus, Spain and is a non paid member of
its Scientific Advisory Committee; Ramon Estruch no conflicts of interest; D. Corella
no conflicts of interest; M. Fito no conflicts of interest and E. Ros has received grants
for research from the California Walnut Commission, Sacramento, CA, U.S. and is a
non paid member of its Scientific Advisory Committee;
Non standard abbreviations: AF, atrial fibrillation; CHD, coronary heart disease; CV,
cardiovascular; CVD, CV disease; DLP, dyslipidemia; EVOO, extra-virgin olive oil;
FFQ, food frequency questionnaire; HTN, hypertension; MeDiet, Mediterranean diet;
MetS, metabolic syndrome; PAD, peripheral artery disease; PREDIMED (PREvención
con DIeta MEDiterránea); RCT,randomized control trial; T2DM, type 2 diabetes
mellitus.
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ABSTRACT
The PREDIMED (PREvención con DIeta MEDiterránea) multicenter, randomized, primary
prevention trial assessed the long-term effects of the Mediterranean diet (MeDiet) on clinical
events of cardiovascular disease (CVD). We randomized 7447 men and women at high CVD
risk into three diets: MeDiet supplemented with extra-virgin olive oil (EVOO), MeDiet
supplemented with nuts, and control diet (advice on a low-fat diet). No energy restriction and
no special intervention on physical activity were applied. We observed 288 CVD events (a
composite of myocardial infarction, stroke or CVD death) during a median time of 4.8 years;
hazard ratios were 0.70 (95% CI, 0.53-0.91) for the MeDiet+EVOO and 0.70 (CI, 0.53-0.94)
for the MeDiet+nuts compared to the control group. Respective hazard ratios for incident
diabetes (273 cases) among 3541 non-diabetic participants were 0.60 (0.43-0.85) and 0.82
(0.61-1.10) for MeDiet+EVOO and MeDiet+nuts, respectively versus control. Significant
improvements in classical and emerging CVD risk factors also supported a favorable effect of
both MeDiets on blood pressure, insulin sensitivity, lipid profiles, lipoprotein particles,
inflammation, oxidative stress, and carotid atherosclerosis. In nutrigenomic studies beneficial
effects of the intervention with MedDiets showed interactions with several genetic variants
(TCF7L2, APOA2, MLXIPL, LPL, FTO, M4CR, COX-2, GCKR and SERPINE1) with
respect to intermediate and final phenotypes. Thus, the PREDIMED trial provided strong
evidence that a vegetable-based MeDiet rich in unsaturated fat and polyphenols can be a
sustainable and ideal model for CVD prevention.
Keywords: Mediterranean diet, Dietary intervention, randomized trials, primary prevention,
atrial fibrillation, peripheral artery disease, stroke, type-2 diabetes.
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Introduction
Cardiovascular (CV) disease (CVD) is the main cause of worldwide premature mortality.
Coronary heart disease (CHD) and stroke ranked first and third, respectively, as the leading
global causes of disability-adjusted years according to the global burden of disease estimates
for 20101. Furthermore, the projections of mortality from CVD for 2030 are dismal
2,3 and
underline the need for preventive strategies as a public health priority. In this context, a high-
quality diet and a healthy lifestyle at middle age are the most important factors for CVD
prevention3-7
. Consequently, the diet-heart hypothesis has been a long-standing tenet in CVD
prevention and nutritional epidemiology during the last 50 years7-8
. Recently, the relevance of
overall high-quality food patterns, rather than the focus on single nutrients and foods, has
emerged as a powerful paradigm to address the inherent complexity of dietary exposures and
to assess their potential CVD preventive effects. Food patterns can be described as the
amounts, proportions, combinations or varieties for the consumption of different foods and
beverages and the frequency with which they are usually consumed. This approach allows the
assessment of synergistic interactions and cumulative effects among different foods and
nutrients, preempts confounding by alternative dietary exposures, avoids some problems of
co-linearity between foods or nutrients and thus provides a strong methodological tool in
nutritional epidemiology9-10
. Even though randomized dietary intervention trials are the
hallmarks for acquiring knowledge on the effects of diet on CVD, most research in the field
of dietary patterns is observational, with some potential for residual confounding and other
possible sources of bias. These limitations have been the subject of ample but probably undue
criticism10,11
.
A weakness of the diet-heart hypothesis is that most of the available experimental research in
the field has not used hard clinical outcomes, but only intermediate risk biomarkers. The
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existence of multiple pathways leading from diet to CVD speaks against the simplistic
approach of giving a high value to changes in any single biomarker. Moreover, the induction
period can vary for the different pathways in which diverse biomarkers are involved, thus
limiting the possibility of assessing multiple biomarker combinations at any time point.
Furthermore, other lesser-known pathways could account for a substantial proportion of
clinical CVD events. The most sensible approach, therefore, in order to investigate the diet-
heart hypothesis is to use hard clinical CVD events as end-points of randomized controlled
trials (RCTs). Most feeding trials, however, are usually short term and rarely include clinical
end-points such as CVD events or death11
. The PREDIMED trial was designed to overcome
both the problem of the single-nutrient approach and the limitations of assessing only
intermediate risk markers. Indeed, the PREDIMED randomized trial used an overall food
pattern as the intervention and assessed hard CVD events as end-points12
providing a high
level of scientific evidence.
Scientific evidence of the cardio-metabolic benefits of the Mediterranean
diet
The abundant and consistent observational evidence that was available to support the benefits
of the Mediterranean diet (MeDiet) and, specifically, of tree nuts and olive oil, on CV health
prompted us to choose this traditional dietary model enriched with olive oil or nuts as the
intervention13-44
. Table 1 summarizes the results of meta-analyses and systematic reviews
assessing the effects of MeDiet on different cardiometabolic outcomes.
The MeDiet is defined as the traditional dietary pattern found in the early 1960s in Greece,
Southern Italy, Spain and other olive-growing countries of the Mediterranean basin. It is a
frugal diet that uses generous amounts of olive oil as main culinary fat and has a high
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consumption of plant-derived foods (fruit, vegetables, legumes, nuts and seeds, and whole
grain cereals); frequent but moderate intake of wine (especially red wine), usually with meals;
moderate consumption of seafood and dairy products (especially yogurt and cheese, but not
whole milk, butter or cream), poultry and eggs; and low consumption of sweet desserts, red
and processed meats. In comparison with other healthy patterns, such as the DASH diet, the
healthy US dietary pattern or the Alternative Healthy Eating Index, the consumption of fruit
and fish is usually higher in the MeDiet, while the consumption of dairy products tends to be
lower. In healthy vegetarian food patterns, meat and seafood are not consumed, but eggs and
dairy are most frequently included. Legumes, nuts/seeds, and processed soy are all higher in a
healthy vegetarian food pattern than in the healthy U.S.-style or Mediterranean-style patterns.
A considerable scientific advantage of the MeDiet over other healthy dietary patterns was the
availability of a previous randomized trial, the Lyon Diet Heart study, conducted in
myocardial infarction survivors (i.e., it was a secondary prevention trial). It showed that a
MeDiet enriched with alpha-linolenic acid, but not olive oil, provided a strong protection
against recurrent CHD45
.
Our hypothesis when designing the PREDIMED trial was that the MeDiet would be
superior to a low-fat diet for primary CVD prevention. This hypothesis had never been tested
previously using a RCT design.
Design and methods of the PREDIMED study
The PREDIMED study was a primary prevention trial which tested the long-term effects of
the MeDiet on incident CVD in men and women at high CVD risk aged 55-75 y (men) or 60-
80 y (women). PREDIMED was a multicenter, nutritional intervention RCT carried out in
Spain from 2003 to 2011. The study was funded by the official Spanish agency for scientific
research, Instituto de Salud Carlos III12
. A web site (www.predimed.es) and the supplemental
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material published together with the final results46
provide full details of the study protocol.
We selected participants from >200 primary care facilities affiliated with 11 recruiting sites.
All participants were at high risk for CVD, but had no history of previous CVD episodes at
enrolment. Criteria for recruitment were the presence of either type 2 diabetes mellitus
(T2DM) or ≥3 risk factors (smoking, overweight or obesity, hypertension/HTN,
dyslipidemia/DLP, and family history of early-onset CVD). Participants were randomized
into one of three diets: 1) MeDiet supplemented with extra-virgin olive oil (EVOO) ;2)
MeDiet supplemented with nuts; and 3) control diet (advice on a low-fat diet).
Full-time registered dietitians delivered the intervention. Throughout the study, participants
attended quarterly individual visits and group sessions in which they were instructed to follow
the allocated diets. Participants also attended quarterly group sessions where they received
written material with information on key Mediterranean foods and seasonal shopping lists,
menus and specific recipes for a typical week. This material was discussed in detail with the
dietitians. Allotments of EVOO (1 L per week, including a minimum of 50 mL/day for
participants and the rest for family needs) or mixed nuts (30 g/day: 15 g walnuts, 7.5 g
almonds and 7.5 g hazelnuts plus extra allocations for the family) were supplied at no cost to
each participant randomly assigned to the MeDiet groups on a quarterly basis during the
group sessions with dietitians. Participants in the control diet group attended similar quarterly
sessions with explanations and written material on the low-fat diet and they received non-food
gifts in these sessions. The three diets were energy-unrestricted and no intervention on
physical activity was conducted.
A validated 14-point MeDiet screener47
was used by dietitians as a tool to both assess actual
adherence to the MeDiet and enhance future adherence. These 14 items were:
1. Use of olive oil as the main culinary fat
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2. Consumption of 4 tablespoons/d of olive oil (including oil used for frying,
salads, out-of-house meals, etc.)
3. Consumption of 2 servings/d of vegetables
4. Consumption of 3 servings/d of fruits
5. Consumption of <1 serving/d of red meat, hamburger or meat products (ham,
sausage, etc.)
6. Consumption of <1 serving/d of butter, margarine, or cream
7. Consumption of <1 serving/d of sweetened and/or carbonated beverages
8. Consumption of 1 serving/d of wine
9. Consumption of 3 servings/week of legumes
10. Consumption of 3 servings/week of fish or shellfish
11. Consumption of <3 servings/week of commercial sweets or pastries (not
homemade), such as cakes, cookies, biscuits or custard
12. Consumption of 3 servings/week of nuts (including peanuts)
13. Preferential consumption of chicken, turkey or rabbit meat instead of veal,
pork, hamburger or sausage
14. Consumption of 2 servings/week of sofrito, a sauce made with tomato and
onion, leek or garlic and simmered with olive oil.
Validated food frequency questionnaires covering 137 foods were collected yearly by the
dietitians. This repeated collection of dietary data allowed us to use the PREDIMED trial as a
unique setting for subsequent cohort studies analyzed as a prospective observational follow-
up study with repeated measurements of diet, thus improving the quality of our dietary
assessment10
.
Fasting blood and spot urine were obtained and serum, plasma and DNA samples were saved.
Objective biomarkers of adherence to the supplemental foods (urinary hydroxytirosol as
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marker of EVOO consumption and plasma α-linolenic acid as marker of walnut consumption)
were determined in random sub-samples.
The pre-specified primary end-point of the trial was incident CVD (a composite of non-fatal
myocardial infarction/MI, non-fatal stroke or CVD death). This composite event occurred in
288 participants during a median follow-up of 4.8 years. The trial was neither powered nor
designed to independently assess each of the three components of the combined end-point.
Secondary outcomes included total mortality, T2DM, metabolic syndrome (MetS), peripheral
arterial disease (PAD), atrial fibrillation (AF), neurodegenerative diseases and major cancers.
An event adjudication committee, whose members were blinded to group allocation, was
responsible for event ascertainment. All participants provided written informed consent and
the protocol was approved by the Institutional Review Boards of all participating centers.
Main results of the PREDIMED trial
We randomized 7447 participants into the three PREDIMED intervention groups. The groups
were well-balanced with respect to their baseline characteristics and pharmacologic
treatments. Though small, between-group differences in some baseline characteristics were
observed, but they were not clinically meaningful. Furthermore, we adjusted all risk estimates
for these variables. The mean age of participants was 67 years, 57% were women and the
mean body mass index was 30 kg/m2. The baseline prevalence of diabetes was nearly 50%
and the prevalence of DLP and HTN was higher than 70% and 80%, respectively.
Compliance with the intervention in the two MeDiet groups was adequate48
. Our
tracking of objective biomarkers in random participant subsamples also indicated compliance
with the intended dietary intervention. However, the achieved absolute difference in
adherence to the MeDiet (according to the 14-item screener) between the intervention group
and the control group was modest, amounting to a maintained difference of 2 points out of 14.
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There were no between-group differences in physical activity during the study. No diet-
related adverse effects occurred.
We assessed the effect of baseline adherence to the 14-point score with respect to the
subsequent incidence of the primary CVD end-point during follow-up49
. As shown in Figure
1, the effect was remarkable. The multivariable-adjusted hazard ratio for participants with a
baseline 14-item screener in the 2nd
-3rd
quintile who scored between 8-9 points was 0.72 (95%
confidence interval [CI]: 0.55-0.94), and for those with the highest adherence (two upper
quintiles, scoring 10-14 points) it was 0.47 (CI: 0.35-0.65).
The observed rates per 1000 person-years for the primary end point were 8.1, 8.0, and 11.2 in
the MeDiet+EVOO, MeDiet+nuts, and control groups, respectively. The unadjusted hazard
ratios were 0.70 (CI, 0.53-0.91) for the MeD+EVOO and 0.70 (CI, 0.53-0.94) for the
MeDiet+nuts. The relative risk reductions, absolute risk reductions and number needed to
treat are shown in Table 2 after multivariable adjustment for sex, age, adiposity variables, and
baseline CVD risk factors. No effect on all-cause mortality was apparent. Significant disease
risk reductions were also observed for incident T2DM (in the subset of participants initially
free of T2DM)50,51
and for other CVD outcomes, such as PAD52
and AF53
. Hence, the
PREDIMED study showed with a RCT design for the first time that a MeDiet supplemented
with either EVOO or nuts is useful in the primary prevention of CVD, PAD, AF, and T2DM
in individuals at high risk.
A beneficial effect of the intervention on MetS status was also observed in the PREDIMED
trial54,55
.In comparison with the control group, participants randomized to either MeDiet were
more likely to show reversion of MetS, with HR 1.35 (CI 1.15–1.58) for the MeDiet+EVOO,
and HR 1.28 (CI 1.08–1.51) for the MeDiet+nuts. Similarly, the PREDIMED MeDiet
interventions were shown to reduce blood pressure and the risk of HTN56,57
and to slow the
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progression of subclinical atherosclerosis, as determined by changes in ultrasound-assessed
carotid intima-media thickness and plaque58,59
.
Number of events hypothetically prevented with the Mediterranean diet
Table 3 shows the number of hard clinical CVD events that could be prevented in a
hypothetical cohort of 1,000 persons undergoing the nutritional intervention with the MeDiet
used in the PREDIMED trial. These results suggest that even a modest intervention with the
MeDiet has the potential to account for a sizable reduction in the number of clinical events in
a relatively short period of time.
Observational studies and trials in the context of the PREDIMED trial
Although some authors have suggested that RCTs with hard clinical events as end-points are
the only solution to circumventing the problems of measurement error inherent to
observational designs in nutritional epidemiology, trials are far from perfect, and also present
considerable limitations10
. These problems include the frequent suboptimal compliance,
losses to follow-up, and the ethical need to prematurely halt the trial when there is sufficient
evidence of benefit, even when the number of observed events is lower than anticipated. In
addition, some degree of contamination of the control group with aspects of the intervention
intended only to the active intervention arms of the trial is unavoidable. Moreover some
exposures or outcomes cannot be assessed with RCTs.
In this context, the symbiosis between properly designed RCTs and large cohort
studies with appropriate and careful control of potentially confounding variables, and due
precautions to improve dietary measurements, are currently the best possible option to
ascertain the health effects of dietary exposures. Adequately designed and tested food
frequency questionnaires (FFQs) have been shown to have acceptable validity when
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compared to reference measures. In addition, adjustment for total energy intake, usually
applying the residuals method along with the use of repeated FFQs in long-term prospective
cohort studies, further improves their validity estimates9,10
.
The availability of validated FFQs of each participant with yearly repeated measurements is a
unique strength of the PREDIMED trial60
. Furthermore, biomarker analyses have
corroborated the validity of our dietary assessment tools61
. Most follow-up studies have
collected measurements of dietary intake only at baseline and this is a limitation in nutritional
epidemiology because diet may change during follow-up. The PREDIMED study has
provided a large body of evidence on the associations between diet and diverse health
outcomes taking advantage of the validated FFQs62-99
.
Mechanisms of protection by the Mediterranean diet
CVD protection by the MeDiet can be explained by a beneficial effect on classical and emergent
CV risk factors56,100-102. Although the underlying mechanisms of protection against CVD by the
MeDiet are not fully understood, the richness of this dietary pattern in antioxidant102
and anti-
inflammatory molecules98
is likely to be relevant. On one hand, this can be due to their anti-
oxidant capacity, such as cell redox state modulating enzyme systems. On the other hand,
nutrients have the capacity of modulating gene and protein expression and, subsequently,
metabolite production. Previous nutrigenomic studies have revealed that the MeDiet has a
protective effect on the expression of several proatherogenic genes involved in vascular
inflammation, foam cell formation, and thrombosis103-104
.
Genomics and the Mediterranean diet
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We investigated whether the effects of the MeDiet or its components might differ depending
on genetic variants. We found several gene-diet interactions in determining both intermediate
and CVD phenotypes105-109
. Suffice it to say that we observed that the association of the
MC4R rs17782313 or the FTO rs9939609 polymorphisms with T2DM were modulated by the
MedDiet107
. When adherence to the MedDiet was low (<9 out of 14 points), carriers of the
variant alleles had higher T2DM risk than wild-type subjects. However, when adherence to
the MedDiet was high (>=9 points), these associations disappeared. These gene-diet
interactions remained after adjustment for BMI. Adherence to the MedDiet was found to
interact with the TCF7L2-rs7903146 (C>T) polymorphism in relation to fasting glucose, total
cholesterol,low-density lipoprotein cholesterol and triglycerides108
. When adherence to the
MedDiet was low, participants with the TT genotype had higher fasting glucose
concentrations and lipids than CC+CT individuals but when adherence was high, these
differences were not apparent. Moreover, TT subjects had a higher stroke incidence in the
control group compared with CC, whereas the dietary intervention with MedDiet was
associated with reduced stroke incidence in TT homozygotes but not CC homozygotes108
.
Both genetic and epigenetic effects on microRNA target site polymorphisms were also
analyzed. A gain-of-function microRNA-410 target site polymorphism (rs13702T>C) in the
lipoprotein lipase gene, interacted with the MedDiet intervention in the association with
triglyceride levels and stroke incidence110
. The interplay between genetic and epigenetic
factors may contribute to better understand some biological mechanisms underlying CVD
progression. Overall these results highlight the relevance of the multi-level omics approaches
to a more comprehensive investigation of the mechanisms accounting for the MedDiet
protective effects.
Conclusions
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The findings from the PREDIMED trial, the Lyon Diet-Heart trial, and many large
prospective cohorts are fully consistent. These large observational and experimental studies
are also supported by mechanistic investigations aimed to assess classical and emergent CVD
risk factors and pathophysiological pathways. Anti-inflammatory effects and reduced
oxidative stress are very likely explanations for the protection observed in the PREDIMED
trial. Taken together, these research findings converge, demonstrating that the traditional
MeDiet offers an affordable, attractive, and easily achievable protection against CVD.
Importantly, these findings suggest that an overall dietary pattern that is rich in high-
unsaturated fat from natural vegetable sources is preferable for CV health than a low-fat diet.
In addition, the MeDiet has been shown to effectively control the residual risk observed after
standard pharmacologic treatment of DLP anomalies and HTN in high-risk individuals.
Taking into account the advanced age of many participants in the PREDIMED trial and in
some of the available cohorts, it can be concluded that it is never too late to improve the food
pattern to improve CV health.
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Acknowledgements
All authors have read and approved the final manuscript. CIBERobn is an initiative of
ISCIII, Spain.
Legends
Figure 1. Association between baseline adherence to the Mediterranean diet and risk of
major cardiovascular events (primary end-point) in the PREDIMED study.
Baseline adherence to the Mediterranean diet (14-point PREDIMED score) and
incidence of the primary end-point in the PREDIMED trial (a composite of myocardial
infarction, stroke or cardiovascular death).
Q1-Q5: quintiles.
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Complete list of PREDIMED INVESTIGATORS
University of Navarra and Osasunbidea (Servicio Navarro de Salud), Primary
Care Centres, Pamplona, Spain: P. Buil-Cosiales, J. Diez-Espino, E Toledo, A.
Garcia-Arellano, M Ruiz-Canela, B. Sanjulian, A. Marti, F.J. Basterra-Gortari, V.
Estremera-Urabayen, A Sola-Larraza, F Barcena-Amigo, C Oreja-Arrayago, M.
Serrano-Martínez, MJ Lasanta-Saez, L Quintana-Pedraza, C Amezcueta-Goñi, P Cia-
Lecumberri, F Artal-Moneva, JM Esparza-López, E Figuerido-Garmendia, H Ruiz-
Millan, R Oses-Primo, JA Tabar-Sarrias, L Fernandez-Urzainqui, MJ Ariz-Arnedo, T
Forcen-Alonso, P Pascual-Pascual, ML Garces, V Extremera, L Garcia-Perez.
University Rovira i Virgili, Reus, Spain: N. Babio, M. Bullo, J. Basora, N. Gonzalez,
C. Molina, F. Marquez, P. Martínez, N. Ibarrola, M. Sorli, J. García Roselló, A, Castro,
F. Martin, N, Tort, A. Isach, M. Guasch-Ferre, M. Baldrich, J.J. Cabre, G. Mestres, F.
Paris, M. Llauradó, R. Pedret, J. Basells, J. Vizcaino, and J. Fernandez-Ballart.
Institute de Recerca Hospital del Mar, Barcelona, Spain: M.I. Covas, S. Tello, J.
Vila, R. de la Torre, D. Munoz-Aguayo, R. Elosua, J. Marrugat, and M. Ferrer.
University of Valencia, Valencia, Spain: J.V. Sorli, P. Carrasco, R. Osma, M. Guillen,
P. Guillem-Saiz, O. Portoles, V. Pascual, C. Riera, J. Valderrama, A. Serrano, E.
Lazaro, A. Sanmartin, A. Girbes, V. Santamaria, C. Sanchez, Z. Pla, and E.
University of Malaga, Malaga, Spain: E Gomez-Gracia, J Fernandez-Crehuet, J.
Wärnberg, R. Benitez Pont, M. Bianchi Alba, R. Gomez-Huelgas, J. Martínez-
Gonzalez, V. Velasco García, J. de Diego Salas, A. Baca Osorio, J. Gil Zarzosa, J.J.
Sanchez Luque, and E. Vargas López.
Hospital Clinic, Institut d’Investigacions Biomediques August Pi i Sunyer,
Barcelona, Spain: M. Serra, A. Perez-Heras, R. Sola, E. Ortega, C. Vinas, R. Casas, L.
de Santamaria, S. Romero, J.M. Baena, M. García, M. Oller, J. Amat, I. Duaso, Y.
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García, C. Iglesias, C. Simon, Ll. Quinzavos, Ll. Parra, M. Liroz, J. Benavent, J. Clos, I.
Pla, M. Amoros, M.T. Bonet, M.T. Martin, M.S. Sanchez, J. Altirruba, E. Manzano, A.
Altes, M. Cofan, C. Valls-Pedret, A. Sala-Vila, and M. Domenech.
University Hospital of Alava, Vitoria, Spain: F. Arós, I. Salaverria, T. del Hierro, J.
Algorta, S. Francisco, A. Alonso, J. San Vicente, A. Casi, E. Sanz, I. Felipe, and A.
Loma-Osorio.
Institute of Health Sciences IUNICS, University of Balearic Islands, and Hospital
Son Espases, Palma de Mallorca, Spain: M Fiol, D Romaguera, M. García -Valdueza,
M. Monino, A. Proenza, R. Prieto, G. Frontera, M. Ginard, F. Fiol, A. Jover, D.
Romaguera and J. García.
Department of Family Medicine, Primary Care Division of Sevilla, Sevilla, Spain:
J. Lapetra, M. Leal, E. Martínez, M. Ortega-Calvo, P. Roman, F. Jose García, P.
Iglesias, Y. Corchado, E. Mayoral, L. Mellado, L. Miró, JM. Lozano and C. Lama.
University of Las Palmas de Gran Canaria, Las Palmas, Spain: L. Serra-Majem, A.
Sanchez-Villegas, J. Alvarez-Perez, E. Diez Benitez, I. Bautista Castaño, I. Maldonado
Diaz, M.J. Férnandez-Rodríguez, F. Sarmiendo de la Fe, C. Simon García , I. Falcon
Sanabria, B. Macias Gutierrez, and A.J. Santana Santana.
Hospital Universitario de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain: X.
Pinto, E. de la Cruz, A. Galera, Y. Soler, F. Trias, I. Sarasa, E. Padres, and E. Corbella.
School of Pharmacy, University of Barcelona, Barcelona, Spain: R.M. Lamuela-
Raventos, M.C. López- Sabater, A.I. Castellote-Bargallo, A. Medina-Remon, and A.
Tresserra-Rimbau.
Primary Care Division, Catalan Institute of Health, Barcelona, Spain: C. Cabezas,
E. Vinyoles, M.A. Rovira, L. García , G. Flores, J.M. Verdu, P. Baby, A. Ramos, L.
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Mengual, P. Roura, M.C. Yuste, A. Guarner, A. Rovira, M.I. Santamaria, M. Mata, C.
de Juan, and A. Brau.
Other investigators of the PREDIMED network: J.A. Tur (University of Balearic
Islands), V. Ruiz-Gutierrez (Instituto de la Grasa, Sevilla), M.P. Portillo (University of
Basque Country) and G. Saez (University of Valencia). All in Spain.
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Table 1. Scientific evidence on the Mediterranean diet.
Systematic reviews assessing the association between adherence to the Mediterranean
diet and cardio-metabolic outcomes.
Systematic review N
(Studies
)
Exposure Outcome Effects of
increased
adherence
to MeDiet*
Comment
Esposito 201131
16
MeDiet
(randomized
trials) Weight loss
-1.75 kg (-
2.86; -0.64)
Greater weight loss with
energy restriction and
longer follow-up
Buckland 2008 38
21
MeDiet
(randomized
trials) Weight loss
Beneficial
(13 studies)
No evidence
(8 studies)
Qualitative systematic
review
Nordmann2011 28
6
MeDiet
(randomized
trials) Risk factors Beneficial
Reductions in BMI, BP,
glucose and CRP
Grosso 201424
58 MeDiet Risk factors Beneficial
Qualitative systematic
review
Schwingshackl2014
18
17 MeDiet
Flow-
mediated
dilatation
WMD
1.86%(0.23-
3.48)
Adiponectin levels also
increased
Schwingshackl
201418
17 MeDiet
High-
sensitivity
CRP
WMD= -1
mg/l(-1.5;-
0.5)
Similar favourable changes
in IL-6 and ICAM-1
Kastorini 201130
50
MeDiet
(randomized
trials)
Metabolic
syndrome
RR = 0.50
(0.29-0.85)**
Significant beneficial
effects were found for each
of the metabolic syndrome
criteria
Esposito 201325 14 MeDiet Metabolic Beneficial Qualitative systematic
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syndrome review
Schwingshackl2014
15
9 MeDiet
Type-2
diabetes
RR = 0·81
(0·73-0·90)
Quantitative meta-analysis:
long-term studies were
fairly homogenous (I2=0%)
and showed a stronger risk
reduction RR = 0·75 (0·68-
0·83)
Koloverou 201416
17 MeDiet
Type-2
diabetes
RR = 0.77
(0.66-0.89)
Quantitative meta-analysis:
subgroups by region,
health status, and degree
of confounding control
rendered similar results.
Esposito 201033
9 MeDiet
Type 2
diabetes and
glycemic
control Beneficial
Qualitative systematic
review
Esposito 2014 23
5
MeDiet
(observational)
Type-2
diabetes Beneficial
Qualitative systematic
review
Esposito 2014 23
5
MeDiet
(randomized trials)
Glycemic
control Beneficial
Qualitative systematic
review
Georgoulis 201420
17 MeDiet
Type-2
diabetes and
other
outcomes Beneficial
Qualitative systematic
review
Roman 200839
20 MeDiet
CVD and risk
factors Beneficial
Qualitative systematic
review
Widmer201414
Not
stated
MeDiet and its
components CVD
RR = 0.95
(0.83-0.97)
Qualitative systematic
review: favourably
compared with
pharmacologic
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interventions
Ros2014 17
Not
stated MeDiet CVD Beneficial
Qualitative systematic
review: the results of the
PREDIMED trial are
presented in the context of
their consistency with
observational results.
Whayne 201419 Not
stated MeDiet CVD Beneficial
Qualitative systematic
review
Sofi2008 37
4
MeDiet (+2/9
points) CVD
RR = 0.91
(0.87-0.95)
This meta-analysis was
subsequently updated
Sofi 201032
8
MeDiet (+2/9
points) CVD
RR = 0.90
(0.87-0.93)
Quantitative meta-analysis:
I2=35%
Sofi2014 21
20
MeDiet (+2/9
points) CVD
RR = 0.90
(0.87-0.92)
Quantitative meta-analysis:
I2=38%
Martínez-González
201422
2
MeDiet
(randomized
trials) CVD
RR = 0.62
(0.45-0.85)
Quantitative meta-analysis:
I2=55%
Martínez-González
201422
16
MeDiet
(observational, +2/9
points) CVD
RR = 0.90
(0.86-0.94)
The heterogeneity
disappeared after removing
3 studies assessing only
fatal cases
Martinez-Gonzalez
200935 5 MeDiet CVD Beneficial
Qualitative systematic
review
de Lorgeril 200836 Not
stated MeDiet CVD Beneficial
Qualitative systematic
review
Rees 201326
11
MeDiet (?)-only
trials CVD No evidence
The selection of trials
apparently had little
connection with the
concept of MeDiet.
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Panagiotakos
200442 6 MeDiet CHD
8% to 45%
relative risk
reduction
Qualitative systematic
review
Psaltoupolou2013
27
22 MeDiet Stroke
RR = 0.71
(0.57-0.89)
Quantitative meta-analysis:
meta-regression suggested
stronger protection among
males.
Tyrovolas 201034
9 MeDiet
CVD and
cancer Beneficial
Qualitative systematic
review
Martinez-Gonzalez
200441
14
Feeding
randomized trials
CVD and
cancer Unknown
The authors support the
case for the urgent need
of a trial such as
PREDIMED
Sofi 200837
8
MeDiet (+2/9
points)
all-cause
mortality
RR = 0.91
(0.89-0.94)
This meta-analysis was
subsequently updated
Sofi2010 32
9
MeDiet (+2/9
points)
all-cause
mortality
RR = 0.92
(0.90-0.94)
Quantitative meta-analysis:
I2=33%
Sofi2014 21
18
MeDiet (+2/9
points)
all-cause
mortality
RR = 0.92
(0.91-0.93)
Quantitative meta-analysis:
I2=47%
Trichopoulou
200043 3 MeDiet
All-cause
mortality
Longer
survival
Qualitative systematic
review
Serra-Majem2006
40 35 MeDiet
A variety of
outcomes Beneficial
Qualitative systematic
review
Trichopoulou2014
44
Not
stated MeDiet
A variety of
effects Beneficial
Opinion of experts around
the world
Maderuelo-
Fernández 201413 14
Interventions to
promote MeDiet
Adherence to
MeDiet Beneficial
Qualitative systematic
review: hard end-points
were not assessed
MeDiet: Mediterranean diet
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(+2/9 points): effects associated with increasing 2 points in a 0 to 9 score of adherence
to the MeDiet.
CVD: cardiovascular disease
CHD: coronary heart disease
RR: Relative Risk (95% Confidence Intervals)
WMD: weighted mean difference
CRP: C-reactive protein
IL-6: interleukin 6
ICAM-1: intercellular adhesion molecule
BMI: body mass index
BP: blood pressure
I2: index to quantify heterogeneity in meta-analyses, please check Higgins et al. BMJ
2003;327:557–60.
*Risk ratios in meta-analyses of epidemiologic studies, usually adjusted for multiple
confounders, compared the highest versus the lowest category of adherence to the
MeDiet. Outcome changes describe the mean changes for the MeDiet versus
comparator diets in meta-analyses of RCTs; only statistically significant changes are
shown. Values between brackets are 95% confidence intervals.
**An apparent erratum was corrected. The authors presented the log of hazard ratio
(95% CI) as -0.69 (-2.16 to -1.16), but this is impossible, the correct upper limit should
probably be -0.16 (as we have assumed).
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Table 2. Relative Risk Reduction, Absolute Risk Reduction and Number Needed to Treat associated with the PREDIMED primary prevention
intervention for several hard clinical events (assuming median follow-up = 4.8 years).
Mediterranean diet supplemented with Extra-virgin olive oil Mediterranean diet supplemented with mixed nuts
Clinical event
Relative Risk
Reduction
Absolute Risk
Reduction
Number needed
to treat
Relative risk
Reduction
Absolute Risk
Reduction
Number needed
to treat
Primary CVD end-point 30% (8.0% ; 46%) 1.34% (0.36% ; 2.05%) 75 (49-281) 28% (4.0% ; 46%) 1.25% (0.18% ; 2.05%) 80 (49-562)
Type 2 diabetes 40% (15% ; 57%) 3.52% (1.32% ; 5.02%) 28 (20-76) 18% (-10% ; 39%) 1.59% (-0.88% ; 3.44%) -
Peripheral artery disease 64% (35% ; 79%) 1.18% (0.64% ; 1.45%) 85 (69-155) 46% (8% ; 68%) 0.85% (0.15% ; 1.25%) 118 (80-679)
Atrial fibrillation 38% (12% ; 55%) 1.54% (0.48% ; 2.22%) 65 (45-206) 10% (-23% ; 34%) 0.40% (-0.93% ; 1.37%) -
Fully adjusted estimates for the hazard ratios from Cox regression models were used to compute the Relative Risks (RR).
The Relative Risk Reduction (RRR) was computed as RRR = (1-RR)%.
The Absolute Risk Reduction (ARR) was computed taking into account the baseline incidence of events in the control group (I0) after a median
follow-up of 4.8 years and applying the estimates for the Relative Risks, i.e. ARR= I0 (1-RR).
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Table 3. Number of expected prevented cases with the PREDIMED primary prevention intervention for several hard clinical events (median
follow-up: 4.8 years) in a hypothetical cohort of 1,000 subjects. Both Mediterranean diet groups were merged together.
Clinical event
Number of prevented cases (95% CI) per 1,000 hypothetical
participants receiving the PREDIMED MeDiet-intervention
Primary CVD end-point 13 (4 to 20)
Type 2 diabetes 26 (7 to 41)
Peripheral artery disease 10 (6 to 13)
Atrial fibrillation 11 (2 to 18)
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Figure 1. Baseline adherence to the Mediterranean diet (14-point PREDIMED score)
and incidence of the primary end-point in the PREDIMED trial (a composite of
myocardial infarction, stroke or cardiovascular death). Q1-Q5: quintiles.